Endocrine therapy is commonly used for treatment of breast cancer in postmenopausal women, especially among patients of the oldest age. The efficacy of endocrine treatment depends on close regulation of breast cell growth by estrogens and peptide growth factors. However, as breast cancer progresses, the disease usually becomes resistant to estrogens, and most patients no longer respond to therapy with antiestrogens. New data show that the growth-regulatory function of estrogens is disrupted in cancer cells with amplification of HER-2 growth factor receptors. Overexpression of HER-2 occurs in 25-30% of breast cancers in postmenopausal women and is associated with the failure of endocrine therapy in the clinic. Understanding the biologic basis of this association may help to improve management and increase patient survival. Specific aims of this project are: I) To confirm the role of HER-2 receptor overexpression in the promotion of estrogen-independent growth and to investigate alternate treatments to prevent human breast cancer progression in preclinical models of postmenopausal breast cancer. Parent breast cancer cells with low- expression of HER-2 and bioengineered daughter-cells with high- expression of HER-2 will be tested for their differential sensitivity to estrogen, tamoxifen and pure antiestrogen. In addition, we will assess the therapeutic advantage of antiestrogen therapy in combination with antireceptor antibodies which down-regulate the HER-2 receptor. 2)To investigate the mechanism for regulation of estrogen receptor (ER) by a growth factor receptor signaling pathway. The study will focus on signal transduction by HER-2 receptor and potential downstream effects on transcription of wild-type and variant ER, on binding and interaction of ER with estrogen-response elements in the nucleus, and on phosphorylation of tyrosine and serine residues in ER in breast cancer cells. Antisense oligonucleotide to ER mRNA will be used to define the possible role-of ER in HER-2-promoted growth. 3)To assess the biologic significance of heregulin, a ligand for activation of HER-2/HER-3 receptors, in breast cancer progression and estrogen-independent growth. Heregulins may be estrogen-induced growth factors. This hypothesis will be tested by measure of hormonal modulation of heregulin mRNA transcription and secretion and by study of heregulIn effects on growth of cells from postmenopausal patients. Anti-heregulin antibodies will also be evaluated as novel antitumor agents. These studies may lead to new hormone therapies in older women with HER-overexpressing breast cancers.